The functional relationship between the ets gene of transforming leukemia virus, E26, and its cellular prototypes has been facilitated by structural comparisons at the nucleic acid and predicted protein levels. The genomic structure of the mouse Ets-1 and Ets-2 genes is being characterized. Sequence alignment of the human and mouse Ets-1 genes has allowed identification of highly-conserved 5' and 3' nucleic acid sequences. Oligonucleotides containing the 5' conserved sequences have been used to identify nuclear binding proteins. Tissue-specific transcription factors have been identified by EMSA and in vitro footprinting. Several binding sites have also been demonstrated by in vivo footprinting. Clones for new transcription factors defined by these analyses have been obtained. A new gene designated ERGB that, although related to ERG at the nucleotide level, has unique properties, including novel chromosome location and a more ubiquitous pattern of gene expression. Like ETS1, the ERGB gene is located on chromosome 11, and is found on the 4q- chromosome resulting from the translocation t(4;11). It has been demonstrated that ERGB protein is a DNA-binding protein that can act as a transcriptional activator and is the human homolog of the murine Fli-1 gene. Qualitative and quantitative changes in mRNA have been detected in some human tumor samples and we are currently in the process of obtaining clones for these transcriptions.